Xavier Delbeuck

My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer's disease.

Theory of mind reasoning-the ability to understand someone elses mental states, such as beliefs, intentions and desires-is crucial in social interaction. It has been suggested that a theory of mind deficit may account for some of the abnormalities in interpersonal behaviour that characterize patients affected by behavioural variant frontotemporal dementia. However, there are conflicting reports as to whether understanding someone elses mind is a key difference between behavioural variant frontotemporal dementia and other neurodegenerative conditions such as Alzheimers disease. Literature data on the relationship between theory of mind abilities and executive functions are also contradictory. These disparities may be due to underestimation of the fractionation within theory of mind components. A recent theoretical framework suggests that taking someone elses mental perspective requires two distinct processes: inferring someone elses belief and inhibiting ones own belief, with involvement of the temporoparietal and right frontal cortices, respectively. Therefore, we performed a neuropsychological and neuroimaging study to investigate the hypothesis whereby distinct cognitive deficits could impair theory of mind reasoning in patients with Alzheimers disease and patients with behavioural variant frontotemporal dementia. We used a three-option false belief task to assess theory of mind components in 11 patients with behavioural variant frontotemporal dementia, 12 patients with Alzheimers disease and 20 healthy elderly control subjects. The patients with behavioural variant frontotemporal dementia and those with Alzheimers disease were matched for age, gender, education and global cognitive impairment. [(18)F]-fluorodeoxyglucose-positron emission tomography imaging was used to investigate neural correlates of theory of mind reasoning deficits. Performance in the three-option false belief task revealed differential impairments in the components of theory of mind reasoning; patients with Alzheimers disease had a predominant deficit in inferring someone elses belief, whereas patients with behavioural variant frontotemporal dementia were selectively impaired in inhibiting their own mental perspective. Moreover, inhibiting ones own perspective was strongly correlated with inhibition in a Stroop task but not with other subprocesses of executive functions. This finding suggests that self-perspective inhibition may depend on cognitive processes that are not specific to the social domain. Last, the severity of the deficit in inferring someone elses beliefs correlated significantly over all subjects with hypometabolism in the left temporoparietal junction, whereas the severity of the deficit in self-perspective inhibition correlated significantly with hypometabolism in the right lateral prefrontal cortex. In conclusion, our findings provided clinical and imaging evidence to support differential deficits in two components of theory of mind reasoning (subserved by distinct brain regions) in patients with Alzheimers disease and patients with behavioural variant frontotemporal dementia.

Vascular Subcortical Hyperintensities Predict Conversion to Vascular and Mixed Dementia in MCI Patients

Background and Purpose— Patients with mild cognitive impairment (MCI) have an increased risk of dementia. The identification of predictors of conversion to dementia is therefore important. The aim of our study was to test the hypothesis that subcortical hyperintensities (SH) are associated with an increased rate of conversion to dementia in MCI patients. Methods— This was an observational study on consecutive MCI patients attending a memory clinic. We assessed SH on a baseline MRI scan, using a semiquantitative rating scale. A multivariable Cox regression model was used to test the association of SH with conversion to dementia. Results— We included 170 MCI patients. The median duration of follow-up was 3.8 years. During this period, 67 patients (39.4%, 95% CI: 32.1 to 46.8%) developed dementia: Alzheimer disease (AD) in 29 patients, dementia with Lewy bodies in 19, mixed dementia in 8, vascular dementia in 7, fronto-temporal dementia in 2, and primary progressive aphasia in 2. SH were not associated with the risk to develop dementia as a whole, including AD. However, the risk to develop vascular or mixed dementia increased significantly with increasing amounts of SH at baseline (HR=1.14 [95% CI: 1.06 to 1.24]), especially periventricular hyperintensities (HR=2.71 [95% CI: 1.60 to 4.58]), independently of medial temporal lobe atrophy, age, gender, vascular risk factors, education, and cognitive functions at baseline. Conclusion— The risk of vascular or mixed dementia, but not of other types of dementia, was significantly increased in MCI patients with a large amount of subcortical hyperintensities at baseline.

Prevalence of Subcortical Vascular Lesions and Association With Executive Function in Mild Cognitive Impairment Subtypes

Background and Purpose— Subcortical hyperintensities (SH) have not been systematically evaluated in mild cognitive impairment (MCI). We sought to describe their frequency and distribution, and to test their association with cognitive characteristics in MCI patients. Methods— We performed standardized neuropsychological tests and an MRI scan in 170 consecutive MCI patients. Medial temporal lobe atrophy and SH, including periventricular, lobar white matter, basal ganglia and infratentorial hyperintensities, were assessed with visual semiquantitative scales. Results— The median age was 68.1 years (range: 45.5 to 87.0), and the median Mini-Mental State Examination score 28.0 (range: 26.0 to 30.0). MCI subtypes were amnestic single domain (21.2%), amnestic multiple domain (52.3%), nonamnestic single domain (21.8%), and nonamnestic multiple domain (4.7%). SH were found in 157 patients (92.6%); periventricular hyperintensities (80.6%) and lobar white matter hyperintensities (83.5%) were the most prominent locations. There was no association between SH and MCI subtypes. Executive dysfunction was independently associated with SH (odds ratio=2.53, 95% CI: 1.20 to 5.32), periventricular hyperintensities (odds ratio=2.51, 95% CI: 1.13 to 5.55), and white matter hyperintensities (odds ratio=2.08, 95% CI: 1.01 to 4.25). Conclusions— The prevalence of SH is high in MCI patients, irrespective of MCI subtypes. SH (especially periventricular hyperintensities, and lobar white matter hyperintensities) are associated with executive dysfunction.

Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer's disease

Background It is essential to detect and then treat factors that aggravate Alzheimers disease (AD). Here, we sought to determine whether or not continuous positive airway pressure (CPAP) therapy for sleep apnoea syndrome (SAS) slows the rate of cognitive decline in mild-to-moderate AD patients. Methods Between January 2003 and June 2011, we included consecutive, mild-to-moderate AD patients (a Mini Mental State Examination (MMSE) score at inclusion ≥15) with severe SAS as determined by video-polysomnography (an apnoea-hypopnoea index ≥30). In this single-blind, proof-of-concept trial, we analysed the mean decline in the annual MMSE score (the main outcome measure) according to whether or not the patients had received CPAP therapy. The decline was computed for each patient and for the first 3 years of follow-up. Results Of the 23 included patients, 14 underwent CPAP treatment. The CPAP and non-CPAP groups did not differ significantly in terms of their demographic characteristics or MMSE score at baseline. The median annual MMSE decline was significantly slower in the CPAP group (−0.7 (−1.7; +0.8)) than in the non-CPAP group (−2.2 (−3.3; −1.9); p=0.013). Conclusions In this pilot study, CPAP treatment of severe SAS in mild-to-moderate AD patients was associated with significantly slower cognitive decline over a three-year follow-up period. Our results emphasise the importance of detecting and treating SAS in this population.

Action and noun fluency testing to distinguish between Alzheimer's disease and dementia with Lewy bodies

The objective of the present study was to establish whether performance in an action fluency task is of value in the differential diagnosis of Alzheimers disease (AD) and dementia with Lewy bodies (DLB). After collecting normative data on performance in an action fluency task and a conventional animal fluency task in a cohort of French-speaking healthy controls, we assessed AD and DLB patients. Only the action fluency score differed significantly between the two demented groups, with DLB patients performing worse than AD patients. However, a composite action and animal fluency score was found to be more effective for discriminating between these two groups.

Bilateral Temporal Glioma Presenting as a Paraneoplastic Limbic Encephalitis With Pure Cognitive Impairment

Introduction:Memory impairment caused by bilateral hippocampal primitive brain tumor is rarely reported. Clinical and MRI features can mimic paraneoplastic limbic encephalitis (PLE), and the differential diagnosis between these 2 entities may be difficult. Case Report:We report the case of a 42-year-old woman presenting with amnesia without neurologic focal signs at clinical examination. The neuroimaging features consisted of bilateral limbic hyperintensities on T2-weighted and FLAIR brain MRI. Despite exhaustive biologic and radiologic investigations, no specific etiology was found. The diagnosis of paraneoplastic limbic encephalitis was suspected, although antineuronal antibodies were negative and no cancer was detected after the first evaluation. Eight months after onset, the memory complaint of the patient increased along with disability in activities of the daily living, the neurologic examination slightly changed with frontal neurologic signs and the brain MRI showed a new cystic lesion in the left hippocampus with enhancement after contrast administration. The left temporal tumor was resected and the neuropathological examination was consistent with gliomatosis cerebri with a focal high grade astrocytoma. Conclusions:This case highlights the need to consider the possibility of infiltrative gliomatosis in patients presenting with features of paraneoplastic limbic encephalitis.

Characterization and prediction of the recognition of emotional faces and emotional bursts in temporal lobe epilepsy

Introduction: The present study sought to characterize and predict the recognition of emotional stimuli (presented in a visual or auditory modality) by patients with temporal lobe epilepsy (TLE). Method: Fifty TLE patients and 50 matched controls performed two emotion recognition tasks (emotional faces and emotional bursts). Neutral stimuli were also presented, and emotional biases were monitored by analyzing errors. Demographic, cognitive, psychobehavioral and (in TLE patients only) clinical and quality of life data were also recorded. Results: Compared with controls, TLE patients were impaired in the recognition of fear expressions in both visual and auditory modality tasks. However, impairments in the two channels were not always concomitant on the individual level. In the visual modality, recognition of disgust and neutral expressions was significantly worse in TLE patients. In the auditory modality, nonsignificant trends toward poor recognition of disgust and neutral expressions were observed. Negative biases were noted in TLE patients; expressions of fear (faces and bursts) were more frequently misinterpreted as disgust, and neutral facial expressions were more frequently misinterpreted as sadness. Impairments in the recognition of facial fear were less pronounced in left TLE patients who (according to structural magnetic resonance imaging, MRI) did not have any brain lesions. In TLE patients, low levels of social support (a quality of life parameter) were associated with worse recognition of facial disgust, and higher levels of apathy were associated with better recognition of neutral faces. Conclusions: TLE patients are impaired in some aspects of emotion recognition with both visual and auditory stimuli, although the differential impact of TLE on these modalities requires further research. These emotional impairments are related to quality of life and psychobehavioral parameters.

Memory loss during lenalidomide treatment: a report on two cases

BackgroundThere are many reports of cognitive dysfunction in patients receiving chemotherapy or targeted therapies. Many antineoplastic agents may be involved in the condition also known as “chemo brain” or “chemo fog”.Case presentationTwo male patients (aged 41 and 70) with multiple myeloma developed severe, rapidly progressing cognitive impairment (mostly involving episodic memory) and loss of independence in activities of daily living during lenalidomide-based treatment. On withdrawal of the drug, one patient recovered normal cognitive function and independence in activities of daily living, whereas mild cognitive impairment persisted in the other patient. The Naranjo Adverse Drug Reaction Probability Scale score was 6 out of 13 for the first patient and 5 out of 13 for the second, suggesting a probable causal relationship between the adverse event and lenalidomide administration.ConclusionLenalidomide may induce particular cognitive disorders (notably episodic memory impairments) in some patients. The drug’s putative neurotoxicity is probably promoted by specific risk factors (such as previous chemotherapy, prior mild cognitive impairment, age and the presence of cerebrovascular lesions).

Low Prevalence and Clinical Effect of Vascular Risk Factors in Early-Onset Alzheimer’s Disease

Background: Determinants of early-onset Alzheimer’s disease (EOAD) are not well known. In late-onset AD, vascular risk factors (VRFs) are associated with earlier clinical manifestation. Objective: The objective of this study was to assess the putative association between VRFs and EOAD. Methods: We studied participants with dementia meeting criteria for EOAD (recruited into the French CoMAJ prospective cohort study from 1 June 2009 to 28 February 2014) and age-, gender-matched controls (ratio 1:3, drawn randomly from the French MONA-LISA population-based survey between 2005 and 2007). Demographic data, VRFs, comorbidities, treatments, and APOE genotypes were compared in multivariable logistic regression analyses. Results: We studied 102 participants with dementia (mean±standard deviation age: 59.5±3.8; women: 59.8%) and 306 controls. Compared with controls, EOAD participants had spent less time in formal education (9.9±2.9 versus 11.7±3.8 y; p < 0.0001), were less likely to be regular alcohol consumers (p < 0.0001), had a lower body mass index (–2 kg/m2; p < 0.0004), and a lower mean systolic blood pressure (–6.2 mmHg; p = 0.0036). The prevalence of APOE ɛ4 allele was higher in participants with dementia than in controls (50% versus 29.4%; p = 0.0002), as was the prevalence of depression (48% versus 32%; p < 0.001). Similar results were observed in multivariable analysis. Compared with EOAD participants lacking VRFs, EOAD participants with at least one VRF had a higher prevalence of depression (29.6% versus 53.3%, respectively; p = 0.03). Conclusion: The prevalence of VRFs is not elevated in EOAD patients (in contrast to older AD patients). Extensive genetic testing should be considered more frequently in the context of EOAD.

Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF biomarkers

BACKGROUND Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). OBJECTIVE The aim of this study was to test the hypothesis of misdiagnoses for these patients. METHOD Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aβ1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. RESULTS In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. CONCLUSION AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.